When IgG4RD Meets Full-House Nephritis: A Diagnostic Crossroads

Introduction: IgG4-related disease (IgG4RD) is an immune-mediated fibroinflammatory condition that can mimic malignancies and other autoimmune disorders. The classic renal manifestation is tubulointerstitial nephritis (TINU), and less commonly, membranous nephropathy. We present a case of presumed IgG4RD with a biopsy consistent with lupus-like nephritis. Case Description: A 55-year-old man presented with fatigue. Two years prior, he had been diagnosed with biopsy-proven IgG4-related sclerosing cholangitis. His creatinine was 7.6 mg/dL from a baseline of 1.2 mg/dL two months earlier. Hemoglobin was 4.8 g/dL and platelets,218K/µL. Liver function tests were normal, except for hypoalbuminemia (2.8 g/dL). Labs showed hemolysis with low haptoglobin, elevated LDH, and schistocytes. A urinalysis revealed proteinuria and microscopic hematuria.Additional testing showed a positive ANA (1:80), hypocomplementemia, positive smooth muscle antibody, and elevated serum IgE and IgG4. ADAMTS13, direct Coombs, anti-dsDNA, anti-cardiolipin antibody, cryoglobulins, PLA2R antibody, anti-SSA/SSB, and ANCA were normal. A kidney biopsy revealed amembranoproliferative GN and full-house immunofluorescence with membranous features without TMA. Discussion: This case shows the diagnostic complexity of IgG4RD, particularly when renal histology is atypical. Elevated IgG4 levels are not diagnostic alone, definitive diagnosis requires characteristic organ involvement and supportive histologic/radiologic findings. Exclusion of other autoimmune conditions is necessary. Our patient met diagnostic criteria for IgG4RD based on prior biliary involvement, IgG4 elevation, and radiology. However, several atypical features complicated the diagnosis including hemolytic anemia of unclear etiology and class IV/V lupus nephritis. Improvement in renal function after steroid therapy may reflect resolution of presumed TINU by the time of biopsy. However, this does not explain the lupus-like glomerular findings. Given the degree of chronicity and fibrosis, rituximab was started for extrarenal disease. IgG4RD is heterogeneous and can overlap with other autoimmune diseases. Timely biopsy is essential in cases with kidney involvement for accurate diagnosis and treatment. Renal pathology may not mirror extrarenal manifestations, underscoring the need for a multidisciplinary approach and consideration of mixed or evolving pathology.